Classic Drug, New Target: Lithium as Disease-Modifying in Alzheimer Dementia

Interest in lithium as a potential disease-modifying therapy for Alzheimer disease has intensified alongside evidence that endogenous brain lithium homeostasis may play an early role in disease pathogenesis.¹ A recent narrative review synthesized more than 20 years of preclinical, neuroimaging, epidemiologic, and early clinical trial data to build the case for lithium's rigorous study in dementia care.² Unlike many investigational Alzheimer therapies, lithium carries decades of clinical familiarity, including well-characterized dosing, safety, and monitoring considerations. The review also highlights lithium's multi-target biological profile, spanning protein clearance, mitochondrial function, and tau pathology, as a potentially meaningful departure from single-pathway drug candidates in the Alzheimer pipeline. Laura Nisenbaum, PhD, discussed with Psychiatric Times the historical and scientific context behind this review, its clinical relevance, and the next steps needed to determine whether lithium can be translated into an effective, biomarker-guided treatment for Alzheimer disease.

Psychiatric Times: First, what context does this review sit in? How does this paper add to the lithium in Alzheimer disease landscape?

Laura Nisenbaum, PhD: The field has been asking questions about lithium for years, and this review is significant because it includes the most up-to-date information and places it in historical context. It synthesizes more than 2 decades of research, including preclinical studies, neuroimaging, epidemiology, and early clinical trials, and makes a coherent case that lithium deserves robust and definitive study into its potential as a disease-modifying therapy.

PT: What findings from this paper are most relevant to the practicing psychiatrist?

Nisenbaum: One of the most clinically relevant points is that lithium is already a familiar medication with decades of clinical experience behind it. That matters because, unlike many investigational Alzheimer therapies, clinicians already understand lithium’s dosing considerations, safety profile, potential side effects, and need for monitoring.

Although, our review does not suggest that lithium is ready for routine use in dementia care. Rather, it highlights why lithium deserves to be studied more rigorously in Alzheimer disease, particularly at low doses and in carefully selected patient populations.

PT: How might lithium function biologically as a disease-modifying agent for dementia?

Nisenbaum: The breadth of biological rationale is intriguing. Lithium appears to act on several biological processes central to Alzheimer disease, including protein clearance, mitochondrial function, and tau pathology. That multi-target profile is significant because Alzheimer disease is not a single-pathway disease. Alzheimer disease is increasingly understood as a multifactorial disease, and a therapy with the potential to address several contributing processes at once is a meaningfully different proposition than most single-target drugs in the pipeline.

Given lithium’s long clinical history, low cost, and global availability, a narrative review like ours helps build the rationale for a serious, well-designed clinical trial.

PT: What would be most beneficial as next steps in researching lithium for dementias?

Nisenbaum:The most immediate need is a robust randomized trial in individuals with mild cognitive impairment (MCI), where intervention may have the greatest impact. That trial should be biomarker-driven, so researchers can determine whether lithium is actually changing the underlying biology of the disease, not simply stabilizing a cognitive test score.

Previous studies of lithium in patients with MCI or dementia have largely tested a type of lithium known as lithium carbonate. A 2025 Nature study suggested that another type of lithium called lithium orotate may have different chemical properties and be more effective in preclinical models.³ Lithium orotate is available as a supplement, but it has not been studied in patients to nearly the same extent as lithium carbonate, so we do not yet know how it compares in terms of safety or effectiveness. Clinical studies are the only way to know whether the early findings translate into real benefit.

That same research also raised the possibility that lithium deficiency itself may be an early event in Alzheimer pathogenesis, which opens a longer-term question: whether intervening before mild cognitive impairment develops could delay or even prevent disease onset altogether. Prevention is one of the most important frontiers in Alzheimer research right now, and the ultimate goal is to prevent the disease before it begins.

Dr Nisenbaum is executive director of drug development at the Alzheimer’s Drug Discovery Foundation.

References

1. Lu Q, Lv H, Liu X, et al. Lithium therapy's potential to lower dementia risk and the prevalence of Alzheimer's disease: a meta-analysis. Eur Neurol. 2024;87(2):93-104.

2. Moore GJ, Bose N, Henter ID, et al. The 25-year evolution of lithium as a disease-modifying agent in dementia. JAMA Psychiatry. 2026.

3. Aron L, Ngian ZK, Qiu C, et al. Lithium deficiency and the onset of Alzheimer’s disease. Nature. 2025;645:712-721.